The focus of this new R21 application is to develop a nanoparticle based noninvasive trans-tympanic membrane delivery system for treating middle ear (ME) infection (otitis media, OM). OM is the most common childhood infection and is a leading reason for pediatric office visits, new antibiotic prescriptions and surgery in young children. US healthcare system expends over $5B annually in treating this disease. OM also has the potential for additional serious and developmental consequences for children due to its propensity to impact hearing. Bacterial infection, long term inflammation and over production of mucins in the ME are hallmarks of the disease. OM is generally treated with systemic oral antimicrobial agents which, in part related to the frequency of treatment, have become far less effective as pathogens has developed antimicrobial resistance to these therapies. These systemic treatments also result in frequent adverse side effects including GI, cutaneous and, at times, life-threatening events. Systemic anti-inflammatory medication, while potentially effective in limiting some of the negative local inflammatory aspects of OM in the ME, such as mucin hyper-secretion and hearing loss, is not generally utilized because of potential negative off-target effects. Currently, no effective methods exist for treating chronic OM except for surgical intervention with tympanostomy tube placement (TTP). Thus, development of more effective approaches to deliver therapeutics to the ME, especially via non- invasive trans-tympanic membrane (TM) drug delivery, to eliminate bacterial infection and control inflammation, while avoiding systemic exposure is of high significance. The impermeability of TM, driven by tight junctions on the epithelial layer has strongly limited the topical delivery efficacy of therapeutics to the ME cavity. Increasing the therapeutic flux through TM is critical for success of topical treatment. Our laboratory has developed a novel delivery system to dramatically enhance penetration of ~100 nm positively charged nanoparticles across the intact tympanic membrane compared to free drugs. Based on this preliminary work, we hypothesize that cationic nanoparticles applied topically in outer-ear can effectively and rapidly translocate therapeutics into the middle ear cavity through the TM via enhanced diffusion. Specifically, in this exploratory project we will synthesize, characterize, and optimize single and dual-agent antibiotic and anti-inflammatory cationic nanoparticle formulations for acute and chronic OM and test the delivery efficacy enhancements of these formulations through the TM using ex vivo and in vivo models.